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Doctoral Degrees (Medicine)

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    Differential effects of early life stress and schizophrenia on the development of impulse control disorder = Imiphumela ehlukene yengcindezi yempilo engasekuqaleni kanye nokusangana ekuthuthukiseni ukulawula isifo esivumbuka kungahlelekile.
    (2024) Oginga, Fredrick.; Mpofana, Thabisile.
    Background: Early life stress (ELS) and parental psychopathology, such as schizophrenia, have profound effect on neurobiological and behavioral outcomes in later life. While previous studies in human have explored the individual effects of ELS and parental schizophrenia (PSZ), this study investigates their interactive effects. Objectives: This study aimed to comprehensively examine the impact of ELS and schizophrenia like symptoms on locomotion, anxiety and depressive like behavior, spatial memory, social interaction and neuro-inflammation in Sprague-Dawley rats. Methods: Male and female Sprague-Dawley pups were randomly assigned to eight groups: control, ELS, Ketamine to induce schizophrenia like symptoms (KSZ), and ELS + KSZ. ELS was induced through prenatal stress and maternal separation (MS), while schizophrenia-like behaviour was induced by ketamine administration (KSZ). Ketamine was administered intraperitoneal to the dams, while subcutaneous to the pups as per previously published studies. Behavioral assay, including open field, Morris water maze, social interaction behaviour, and sucrose preference test, was conducted. Neuro-inflammation was through quantification of glial fibrillary acidic protein astrocytes density and inflammatory biomarkers. Results: ELS and KSZ on dams exhibited enduring effects on particularly psychomotor retardation (p < 0.05). Anxiety and depressive like behavior was elevated in the ELS (p = 0.023) and KSZ on dams (p =0.017) groups compared to controls. The combined ELS and KSZ groups showed the highest anxiety and depressive like outcomes (p = 0.006). Additionally, spatial memory and cognitive impairment in pups were observed due to the combined impact of ELS and KSZ, which was associated with a decrease in astrocyte density and dysregulation of neuro-inflammatory markers (p < 0.05). Conclusion: This study highlights the interactive effects of ELS and KSZ on behavior, neurodevelopment, and neuro-inflammation in rats. Both ELS and KSZ in parents were linked to anhedonia, subsequently anxiety-like behavior, and ultimately psychomotor, spatial memory, and cognitive decline in rats. Positive parenting was associated with astrocyte regeneration (p < 0.05) and cognitive improvement. Understanding these complex interactions provides insights into the challenges associated with these stressors and offers potential therapeutic avenues. Iqoqa. Isendlalelo: ingcindezi ekuqaleni kwempilo kanye nobuzali ekuziphatheni kwesifo sengqondo, njengokusangana, kuba nomphumela omkhulu ohlelwenimizwa kanye nemiphumela yokuziphatha ngokuhamba kwesikhathi empilweni. Izifundo ezedlule ngomuntu ziyiphenyile imiphumela ngomuntu mayelana nengcindezi ekuqaleni kwempilo kanye nobuzali ekuphazamisekeni kwengqondo (PSZ). Lolu cwaningo luphenya imiphumela ethelelanayo. Izinhloso: lolu cwaningo luhlose ngokubanzi ukucwaninga imiphumela yengcindezi ekuqaleni kwempilo kanye nokusangana njengezimpawu zokudlathuzela, ixhala kanye nokuziphatha okunobukhwantalala, ukugcinwa kolwazi engqondweni, ukuphilisana ngokwenhlalo kanye nokuvuvukala kwemizwa yengqondo ngokukaSprague-Dawley emagundaneni. Izindlelakwenza: imidlwane yenduna neyensikazi kaSprague-Dawley yakhethwa ngokungahlelekile yanikezwa amaqoqa ayisishiyagalombili: ukulawulwa, i-ELS, Ketamine ukulandela ukusangana njengezimpawu i-KSZ, kanye ne-ELS+KSZ. I-ELS yalandelwa ngokwengcindezi engaphambi kokuzalwa ngesikhathi sokumitha nokuhlukaniswa nonina (MS), ngesikhathi ukuziphatha okusakusangana kwalandelwa ukusetshenziswa kweketamine (KSZ). Iketamine yafakwa ngaphakathi ontwentwesini lwenxasisu yemidlwane esemadamini, ngesikhathi futhi ifakwe ngaphansi kwesikhumba semidlwane njengokusho kocwaningo olushicilelwe ngokwedlule. Ukuziphatha ngokuhlola ingqondo, kufaka insimu evulekile, amanzi amazombe ngokukaMorris, ukuziphatha ngokwenhlalo, kanye nesivivinyo esikhethekile sikashukela, kwenziwa. Ukuvuvukala kwaba ngenxa yequantification yeglial fibrillary yensiza zakhamzimba nokugqishelana kwe-astrocytes kanye nokuvuvukala kwebiomarkers. Imiphumela: Ixhala kanye nengcindezi njengokuziphatha kwaphakanyiswa kuyo i-ELS (p=0.023) and KSZ emadamini (p=0.017) yamaqoqo yaqhathaniswa nabaqashelwe. Ukuhlanganiswa kwe-ELS kanye neKSZ kwatshengisa ixhala elikhulu kanye nengcindezi njengemiphumela (p=0.006). Ngokunezezela, isikhala ngokukhumbula kanye nokulimaza umqondo kwafakelwa izibuko ngenxa yokuhlangana kwesisindo se-ELS kanye neKSZ, okumataniswa nekwehla kwesisindo se-astrocyte kanye nokungalawulwa kwezinkomba zokuvuvukala ngokomqondo (p<0,05). Isiphetho: lolu cwaningo lugqamisa imiphumela ethelelanayo ye-ELS kanye ne-KSZ ekuziphatheni, ukuthuthuka ngokwasengqondo, nokuvuvukala kwengqondo emagundaneni. Kokubili i-ELS kanye ne-KSZ kubazali kwaxhunyaniswa ne-anhedonia, kwalandela ukuziphatha okusaxhala, kwasekuthi ekugcineni ubudlelwanokusebenza kwengqondo nomzimba, ukugcinwa kolwazi engqondweni, nokufadalala kwenqubokucabanga emagundaneni. Ubuzali obuhle kwamataniswa nokuvuselelwa kwe-astrocyte (p<0,005) kanye nokubangcono komqondo. Ukuqonda ukuthelelana okudidayo kokuphilisana kwanikeza ulwazi mayelana nezinselelo ezimataniswa nezimbangangcindezi kwanikeza namathuba okwelapha okungase kwenziwe.
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    Effect of HIV-1 subtype C Transactivator of transcription (Tat) A21P variant on TAR binding ability, nuclear levels of active positive transcription elongation factor b (P-TEFb) and viral latency = Umthelela we-HIV-1 subtype C Transactivator of transcription (Tat) A21P okuhlukile ekhonweni lokubopha i-TAR, amazinga enyukliya we-active transcription elongation factor b (P-TEFb) kanye neviral latency.
    (2023) Mkhize, Zakithi Zinhle.; Madlala, Paradise Zamokuhle.
    The HIV-1 Transactivator of transcription (Tat) enhances the ability of the viral promoter 5’ long terminal repeat (LTR) to drive viral gene transcription and is important for HIV-1 pathogenesis. Tat binds to the transactivator RNA (TAR) element of the 5’LTR and subsequently recruits the host positive transcription elongation factor b (P-TEFb) for efficient viral gene transcription. Inter- and intra-subtype Tat genetic variation that translates to functional differences has been reported. Specifically, HIV-1 subtype C (HIV-1C) exhibiting Alanine at position 21 of the Tat protein (TatA21) was reported to be associated with reduced LTR transcriptional activity compared to Tat exhibiting Proline at position 21 mutation (TatP21). However, the effect of Tat variation on its ability to recruit P-TEFb is unknown. Therefore, this study seek to determine the effect of HIV-1 subtype C TatA21 mutant on the ability of Tat to recruit P-TEFb to 5’ LTR to enhance viral gene transcription. To this effect, site-directed mutagenesis (SDM) was performed on the Plasmid pcDNA3.1(+) HIV-1C BL43/02 TatA21 to introduce TatP21 alone or together with other mutations using designed primers and the Q5 DNA polymerase kit. The effect of Tat mutations was measured using Tat transactivation assay where the luciferase activity was the measured output in TZM-bl cell lines and the impact of TatA21 was further assessed on ability of the LTR to drive GFP and Gag expression in Jurkat and A72 cells respectively. Next, protein modelling was performed using Hdock software, followed by RNA immunoprecipitation (RNA IP) was performed using stably expressing TatA21 and TatP21 in Jurkat cells. Lastly, co-immunoprecipitation of TatA21 and associated with significantly reduced LTR transcription activity compared to TatP21 (p = 0.0004). TatA21 resulted in had significantly lower GFP expression Jurkat cells (p = 0.0439) and lower Gag expression in A72 cells compared to TatP21. Although TatA21 reduced the LTR transcription activity compared to TatP21, protein modelling using Hdock software revealed that TatA21 and TatP21 protein structures were the same. Consistently, molecular docking showed that TatA21 had a lower binding affinity than TatP21. The RNA IP showed that TatA21 had significantly reduced affinity to bind to TAR compared to TatP21 (p = 0.0151). Moreover, TatA21 and TatP21 formed a complex with cycT1 and CDK9. Taken together, our data shows that HIV-1C TatA21 significantly reduced its transactivation activity but does not affect its ability to recruit P-TEFb. Interestingly, TatP21 is able to bind TAR more efficiently than TatA21 thus revealing a possible mechanism but which the reduced functionality of SDMs and patient derived TatA21 variants was observed. The effect of TatA21 and TatP21 on the propensity of HIV-1 latency development or reversal. To this effect, a recombinant viral vector exhibiting either TatA21 (C731CTatA21C) or TatP21 (C731CTatP21C) were generated. The C731CTatA21C or C731CTatP21C were separately co-transfected together with VSV-G and R8.91 into Jurkat cells for virus production. This virus was then used to infect Jurkat cells for 3 days. Followed by cell sorting of GFP- cells, which represented either truly negative or latently infected cells was then performed. We were able to successfully generate C731CTatA21C virus and characterized it to a 1.2% reactivation. However, the generation of C731CTatP21C recombinant viral vector was unsuccessful and thus could not be used for comparison. Future studies should involve the characterization of TatP21 in the propensity of latency development and/ or reactivation. Iqoqa. Iphrotheni eyaziwa ngeTransactivator of transcription (Tat) le-HIV-1 inamandla okuthuthukisa amandla egciwane 5’ le-LTR ukulawula ukuhlonzwa kofuzo lwegciwane futhi ibalulekile ekwelashweni kokukhula kwe-HIV-1. I-Tat ihlanganisa izinhlasiyana ze-RNA (TAR) ye-5'LTR futhi ikwazi ukudonsa i-P-TEFb ukuze ihlonze ngempumelelo isakhi sofuzo. Ukuhlukahluka kofuzo kwangaphakathi nokwangaphandle ekuhlonzweni komehluko nakho kuveziwe. Ngokukhethekile, uhlobo C lwe-HIV-1 (HIV-1C) ebonisa i-alanine endaweni engu-21 yephrotheni i-Tat (TatA21) kubikwe ukuthi ihlotshaniswa nomsebenzi wokuhlonza oncishisiwe we-LTR uma kuqhathaniswa ne-Tat ebonisa iproline ekuguqulweni kwe-21ye-Tat (TatP21). Nokho, umthelela wokuhluka kwe-Tat ekuphumeleni kwayo ukudonsa i-P-TEFb awaziwa. Ngakho-ke, lolu cwaningo beluhlose ukuhlonza umthelela we-HIV-1 lohlobo C lwe-TatA21 eguquguqukayo emandleni e-Tat okuhlonza i-P-TEFb kuya ku-5’ LTR ukuze kuthuthukiswe ukuhlonzwa kofuzo lwegciwane. Kulokhu, isite-directed mutagenesis (SDM) yenziwa kwiPlasmid pcDNA3.1(+) HIV-1C BL43/02 TatA21 ukwethula i-TatP21 iyodwa noma kanye nezinye izinguquko kusetshenziswa amathuluzi aklanyelwe kanye neDNA ye-Q5. Umthelela wokuguqulwa kwe-Tat ukalwe kusetshenziswa i-Tat lapho umsebenzi weluciferase wawungumphumela olinganiselwe emigqeni yenhlasiya ye-TZM-bl futhi umthelela we-TatA21 wabuye wahlolwa mayelana nokuphumelela kwe-LTR uhlonza i-GFP ne-Gag ezinhlasiyeni zeJurkat nama-A72 ngokulandelanayo. Okulandelayo, ukubheka amaprotheni kwenziwa kusetshenziswa isofthiwe ye-Hdock, kwalandelwa yi-RNA immunoprecipitation (RNA IP) kwenziwa kusetshenziswa okuveza ngokuzinzile i-TatA21 ne-TatP21 ezinhlasiyeni zeJurkat. Okokugcina, ico-immunoprecipitation ye-TatA21 ne-TatP21 yenziwe nge-cycT1 ne-CDK9. Imiphumela yethu ibonisa i-TatA21 eguquguqukayo iyodwa ihlotshaniswe nomsebenzi wokuhlonzwa kwe-LTR owehliswe kakhulu uma kuqhathaniswa ne-TatP21 (p = 0.0004). I-TatA21 iholele ekutheni ibe nezinhlasiya ze-GFP yeJurkat ephansi kakhulu (p = 0.0439) kanye ne-Gag ephansi ezinhlasiyeni ze-A72 uma kuqhathaniswa ne-TatP21. Nakuba i-TatA21 yehlise umsebenzi wokuhlonzwa kwe-LTR uma kuqhathaniswa ne-TatP21, ukubhekwa kwamaprotheni kusetshenziswa isofthiwe i-Hdock kuveze ukuthi izakhiwo ze-TatA21 ne-TatP21 zazifana. Ngokuvumelanayo, ukuhlonzwa kwezinhlasiya kubonise ukuthi i-TatA21 inobudlelwane obubophezelayo obuphansi kune-TatP21. I-RNA IP ibonise ukuthi i-TatA21 inciphise kakhulu ukuhambisana ukuze izibophezele kwi-TAR uma kuqhathaniswa ne-TatP21 (p = 0.0151). Ngaphezu kwalokho, i-TatA21 ne-TatP21 bakhe inkimbinkimbi ene-cycT1 ne-CDK9. Sekuhlangene, imiphumela yethu ibonisa ukuthi i-HIV-1C TatA21 iwunciphise kakhulu umsebenzi wayo wokwenza izinto kodwa ayithinti impumelelo yayo yokuhlonza i-P-TEFb. Kuyajabulisa ukuthi i-TatP21 iyakwazi ukuhlanganisa i-TAR kahle kakhulu kune-TatA21, ngaleyo ndlela iveze indlela engase ibe khona kodwa okuye kwabonwa ukusebenza okuncishisiwe kwama-SDM kanye nokuhluka okutholwe esigulini se-TatA21. Umthelela we-TatA21 kanye ne-TatP21 ekuthembekeni kokuthuthukiswa kokubambezeleka kwe-HIV-1 noma ukuguqulwa. Kulokhu, inhlanganisela yegciwane ekhombisa i-TatA21 (C731CTatA21C) noma i-TatP21 (C731CTatP21C) yenziwe. I-C731CTatA21C noma i-C731CTatP21C yadluliselwa ngokuhlukana ndawonye ne-VSV-G kanye ne-R8.91 kuzinhlasiya zeJurkat ukuze kukhiqizwe igciwane. Leli gciwane labe selisetshenziselwa ukuthelela izinhlasiya zeJurkat izinsuku ezi-3. Kulandelwa ukuhlungwa kwezinhlasiya ze-GFP, okwakumele izinhlasiya ezingezinhle ngempela noma ezisanda kungenwa amagciwane kwase kwenziwa. Sikwazile ukukhiqiza ngempumelelo igciwane le-C731CTatA21C futhi silibeke ku-1.2%. Nokho, ukukhiqizwa kwe-C731CTatP21C akuphumelelanga, ngakho-ke akukwazanga ukusetshenziselwa ukuqhathanisa. Ucwaningo lwangomuso kufanele luhlonze ubunjalo be-TatP21 ekuthambekeni kokuthuthukiswa kokubambezeleka nokusebenza kohlelo lokwelapha.
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    Evaluation of laboratory tests for COVID-19 in South Africa = Ukuhlaziya iZivivinyo zaseLabhorethri ze-COVID-19 eNingizimu Afrika
    (2023) Samsunder, Natasha.; Kharsany, Ayesha Bibi Mahomed.; Sivro, Aida.
    The emergence of SARS-CoV-2 prompted urgent needs for accurate diagnosis, management, and containment strategies. This study evaluated diagnostic tests, including point-of-care (POC) tests, to aid in rapid diagnosis across different stages of COVID-19 in South Africa. A scoping review highlighted the variability in test performance, with no single assay achieving optimal sensitivity and specificity simultaneously. Sensitivity was influenced by the timing of sample collection, emphasizing the importance of early sampling. Rapid antigen tests were evaluated against RT-PCR, revealing reasonable sensitivity, especially in samples with lower Ct values and within the first week of symptom onset. However, performance varied across SARS-CoV-2 variants. Notably, PanbioTM and SD Biosensor tests maintained high sensitivity and specificity across different variants, including Omicron sub-lineages. Additionally, the study explored alternative sample types, such as saliva, finding comparable results to nasopharyngeal swabs. Serological tests were also assessed, with the Orient Gene Rapid test showing comparable performance to standard assays, while the MILLIPLEX® MAP Kit demonstrated higher detectability. Overall, despite extensive testing efforts, the sensitivity of diagnostic tests remained limited, underscoring the need for improved performance to effectively diagnose and manage SARS-CoV-2 infections and limit transmission. These findings provide valuable insights for enhancing testing strategies in South Africa and globally amidst evolving pandemic challenges. Iqoqa. Ukuqubuka kwe-SARS-CoV-2 kwaphusha izidingo eziphuthumayo zamasu okuhlonza isifo okuyikho, ukulawula nokunqanda. Lolu cwaningo lwahlola izivivinyo, okufaka nezivivinyo ezaziwa ngelepoint-of-care (POC), ukusiza ukuhlonza isifo ngokushesha ezigabeni ezehlukene ze-COVID-19 eNingizimu Afrika. Ukubuyekeza umumo kwagqamisa ukwehlukahlukana ekuhloleni ukusebenza, kungekho neyodwa i-asayi efikisa ekuzweleni okukhulu nasekuqondeni kanyekanye. Ukuzwela kwakudalwa yisikhathi sokuqoqwa kwesampula, kugcizelelwa ukubaluleka kokuqoqwa kwamasampula kwasekuqaleni. Izivivinyo eziningi zedalasihlungu zahlaziywa ziqhathaniswa ne-RT-PCR, okuveza ukuzwela okuzwakalayo, ikakhulukazi emasampuleni ane-Ct ephansi esontweni lokuqala lokubonakala kwezimpawu. Kodwa, ukusebenza kwehlukana ngokwezinhlobo ze-SARS-CoV-2. Okuqaphelekayo, yi-v Notably, PanbioTM nezivivinyo ze-SD Biosensor ezasimama ngokuzwela okukhulu namavariyenti ehlukene, okufaka nama-Omicron sub-lineages. Ukwengeza, ucwaningo lubheke ezinye izinhlobo zamasampula, njengamathe, ukuthola imiphumela eqhathaniseka nemisubelo yenasopharyngeal. Izivivinyo zeseroloji nazo zahlolwa, kanye nesivivinyo se-Orient Gene Rapid okukhombisa ukusebenza okuqhathanisekayo nama-asayi asezingeni, nakuba i-MILLIPLEX® MAP Kit yakhombisa ukutholakala ngezinga eliphezulu. Ngaphezu kwalokho, nakuba kunemizamo yokuhlola okunzulu, ubuthaka bezivivinyo eziyinhlonzasifo zazilokhu zincane, ukuthola okungaphansi isidingo sokusebenza okuphuculiwe ukuze kuhlonzwe ngendlela futhi kulawulwe ukutheleleka nge-SARS-CoV-2 bese kunqanda ukwedluliseka. Lokhu okutholakele kuhlinzeka imibono enesisindo ukuphucula amasu okuhlola eNingizimu Afrika nasemhlabeni jikelele ezinselelweni zobhubhane eziguquguqukayo.
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    Immune biomarkers of pulmonary tuberculosis treatment response and disease severity among HIV-infected and uninfected individuals from Kwazulu-Natal, South Africa.
    (2023) Rambaran, Santhuri.; Sivro, Aida.; Naidoo, Kogieleum.
    Background: Tuberculosis is one of the major causes of morbidity and mortality worldwide. The COVID -19 pandemic has had a devastating impact on TB, contributing to increased incidence of both TB and drug-resistant TB. Identification of host immune biomarkers of TB risk, treatment outcome and disease severity are key to the development of more efficient diagnostics and treatment modalities. There is an urgent need for accurate and easily detectable non-sputum-based biomarkers that can correlate with the activity or burden of Mycobacterium tuberculosis. Here, we characterised soluble and cellular phenotypes during active TB and TB/HIV co-infection and assessed their associations with time to negative culture conversion and disease severity. Methods: The study was performed utilizing stored plasma and peripheral blood mononuclear cells from the Improving Retreatment Success (IMPRESS) trial. Multiplex immunoassays and ELISAs were used to evaluate 24 cytokine and chemokine expression during active TB (n=132). Flow cytometry was used to evaluate phenotypic profiles of monocytes, dendritic cells (n=90) and CD4+ T cells (n=75). A Cox proportional hazards and logistic regression models were used to assess the associations between the measured cytokines and chemokines, phenotypic profiles of monocytes, dendritic cells and CD4+ T cells and time to negative culture conversion and lung cavitation in individuals with TB and TB/HIV co-infection. Results: We identified soluble inflammatory signatures of treatment response and disease severity. IP-10 expression during active TB was associated with increased odds of sputum culture conversion by 8-weeks in the total cohort and among the HIV-infected individuals. Increased MCP-3 expression was associated with a shorter time to culture conversion in the total cohort. While among the HIV-infected individuals, higher expression of IL-1RA, IP-10 and IL-1α associated with a shorter time to culture conversion. Higher expression of IL-6 was significantly associated with shorter time to culture conversion and increased risk of lung cavitation in the overall cohort and among TB/HIV co-infected individuals. Additionally, higher IL-1RA expression was associated with the presence of lung cavitation in the total cohort and in HIV-infected individuals. We observed distinct monocyte and dendritic cell profiles in TB/HIV co-infection. Individuals with TB/HIV co-infection had a significantly higher percentage of total monocytes and dendritic cells compared to healthy controls. Increase in CCR2, CD11b and CD40 was associated with active TB while decrease in CX3CR1 and increase in CD163 was associated with HIV infection. Expression of CX3CR1 on non-classical monocytes was associated with longer time to culture conversion while expression of CD86 on intermediate monocytes was associated with presence of lung cavitation. With respect to CD4+ T cells HIV positive individuals with active TB had significantly lower percentage of CD4+ T cells and significantly higher proportion of activated CD4+ T cells compared to TB and healthy control groups. Percentage of CD4+ T cells was significantly associated with increased risk, while the percentage of activated CD4+ T cells was associated with decreased risk of lung cavitation. Integrin α4β7 expressing CD4+ T cells were increased in TB/HIV compared to TB group and was associated with longer time to TB culture conversion in co-infected individuals. Conclusion: The data from this study provides valuable insight into the role that plasma immune biomarkers, monocytes, dendritic and CD4+ T cells play in TB treatment response and disease severity in active TB and TB/HIV co-infection. Iqiqa. Isendlalelo: Isifo sofuba, ituberculosis (TB) singenye yezimbangela zokugula nokufa emhlabeni wonke. Ukutholwa kwezimpawu ezikhombisa ukuba sengcupheni yesifo sofuba, Imiphumela yokwelashwa kanye nezinga lokugxila kwesifo kungasiza kakhulu ekwakhiweni kwezinsiza zokuhlola ngempumelelo kanye nezindlela zokwelapha. Kunesidingo esiphuthumayo sezinkomba ezinembayo nezibonakala kalula ezingahlangene nezikhwehlela ezihambisana nokwenziwa yigciwane noma ezingakhombisa umthwalo wegciwane lesifo sofuba. Kulolu cwaningo kwabhekwa izimpawu ezincibilikayo namacellular phenotypes kulabo abane-TB noma inhlanganisela ye-TB ne-HIV kwase kuhlolwa ukuhambisana kwako ngokuhamba kwesikhathi kuze kufike lapho igciwane lofuba lingasaveli kanye nezinga lokujula kwesifo. Izindlela zokuqhuba ucwaningo: Lolu cwaningo lwenziwa ngokuba kusetshenziswe okusegazini okwaziwa ngeplasma kanye namaperipheral blood mononuclear cells ayetholakale ekuvivinyweni okwaziwa nge-Improving Retreatment Success (IMPRESS). Kwasetshenziswa neMultiplex immunoassays kanye nama-ELISA ukuhlola icytokine nechemokine kulabo asebengenwe yi-TB. Kwasetshenziswa neflow cytometry ukuhlola isimo nobunjalo bamamonocytes, amadendritic cells kanye nama-CD4+ T cells. Izindlela ezaziwa ngamacox proportional hazards kanye nelogistic regression zasetshenziswa ukuhlola ukuhlobana phakathi kwamacytokines, amachemokines, amaphenotypic profiles amamonocytes, amadendritic cells kanye namaseli e-CD4+ T nesikhathi sokushabalala kofuba kanye nokuhlaseleka kwamaphaphu kulabo abane-TB noma inhlanganisela ye-TB ne-HIV. Imiphumela: Ucwaningo lwahlaziya imiphumela yenhlanganisela ye-TB ne-HIV kusetshenziswa okuyizimpendulo ezikaliwe nokwaholela ekutholakaleni kwezindlela ezintsha lapho ushintsho oludalwe yi-HIV luvimbela ukulawulwa kwe-Mtb. Kwatholakala ukuthi i-IP-10 kanye ne-IL-6 yizona zinkomba zokuba khona kwe-Mtb emzimbeni kanye nezinye izifo ezivela ngoba umzimba uzama ukuzivikela kubantu abanesandulela ngculazi nalabo abangenaso. Kwabonakala ukwahluka kwezinga eliphezulu mayelana namamonocyte, amadendritic cell subsets kanye namaphenotypes ngesikhathi sokuhlasela kwe-TB kanye ne-TB/HIV okwaba nomphumela wokugudluka kwamaseli, ukunyakaziseka kwezicutshana, kanye nokusebenza kwezindlela zokuzivikela ezihambisana nezimo nokwaletha inguquko ekulweni namagciwane esifo sofuba nezinye izifo. Ekugcineni, kwatholakala iqhaza elisha elibanjwa amaseli e-integrin α4β7 CD4+ T ekwelapheni isifo sofuba: Le integrin α4β7 yanyusa ama-CD4+ T cells kulabo abanenhlanganisela ye-TB ne-HIV uma beqhathaniswa nalabo abane-TB kanti lokhu kwamanyaniswa nokuhlolwa Isikhathi eside kwalabo abasulelekile. Isiphetho: Imininingo etholakale kulolu cwaningo inikeza ukuqonda kabanzi okubalulekile ekusebenzeni kwamaplasma immune biomarkers, amamonocytes, amadendritic kanye namaseli e-CD4+ T ekutheni imithi yokwelapha i-TB izwela kanjani kanye nobunzima besifo kulabo abane-TB nabanenhlanganisela ye-TB ne-HIV.
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    Inflammation and cellular immune phenotypes in TB/HIV co-infection = Ukuvuvukala nezinswebu zamasosha omzimba ezinhlayiya ku-TB/HIV.
    (2023) Maseko, Thando Glory.; Sivro, Aida.; Archary, Derseree.
    South Africa has the highest burdens of TB and HIV. HIV induced inflammatory and immune changes are known to increase the risk of TB recurrence and lead to poor disease outcome in co-infected patients. Here we characterised soluble inflammatory, NK and CD4+ T cell profiles in TB and TB/HIV disease. We utilized peripheral blood specimens from the CAPRISA 011 IMPRESS study to characterize NK and memory CD4+ T helper cell phenotypes during active TB and post TB treatment in individuals with or without HIV co infection. We also characterized the effects of these phenotypes on mycobacterial clearance and TB disease severity measured by the presence of lung cavitation. We additionally characterised plasma cytokine/chemokine markers of cavitary disease in drug-resistant TB patients from the CAPRISA 020 InDEX study. TB/HIV co infection led to the expansion of functionally impaired CD56neg NK cell subset. TB treatment completion resulted in restoration of total NK cells, NK cell subset redistribution and downregulation of several NK cell activating and inhibitory receptors. Higher percentage of peripheral CD56bright cells was associated with longer time to culture conversion, while higher expression of NKp46 on CD56dim NK cells was associated with lower odds of lung cavitation in the overall cohort and the TB/HIV co infected participants. With regards to memory CD4+ T cell responses, TB/HIV co infection led to higher percentage of Th2 cells, α4β1 and α4β7 integrin expressing memory CD4+ T cells, and lower percentage of Th9 cells. Increased IL-6 expression during MDR/XDR-TB was associated with higher risk of lung cavitation in CAPRISA 020 participants. Additionally smoking and previous history of TB were associated with increased risk of cavitary disease while HIV and higher BMI were associated with reduced risk of cavitation during MDR/XDR TB. We identified distinct changes in systemic inflammatory and NK cell and memory CD4+ T cell populations with respect to active disease, treatment completion, bacterial clearance and disease severity in TB and TB-HIV co-infected individuals. These results highlight biologically plausible and novel mechanisms by which concurrent HIV infection impairs the host immune control of Mtb infection. Iqoqa. INingizimu Afrikha inomthwalo omkhulu we-TB ne-HIV. I-HIV ifike nokuvuvukala nezinguquko kumasosha omzimba okwaziwa njengokukhulisa ubungozi bokubuya kwe-TB okuholela emiphumeleni emibi yesifo ezigulini eziphethwe nangezinye izifo. Lapha sibona ukuvuvukala okuncibikalayo, i-NK ne-CD4+ ubunjalo bezinhlayiya zika-T ezifweni ze-TB ne-HIV. Sasebenzisa izimelabunjalo zegazi ezingasekugcineni ocwaningweni lwe-CAPRISA 011 IMPRESS ukuze kubonakale i-NK nememori ye-CD4+ yenswebu yenhlayiya engumsizi ka-T ngesikhathi i-TB isenamandla nangemuva kokwelashelwa i-TB kulowo osuke enayo noma engenayo i-HIV nezinye izifo. Sichaza nomthelela wezinswebu zokucaciswa kwemycobacterial nokwenzeka ngamandla kwesifo se-TB okulinganiswa ngobukhona bezimbobo emaphashini. Sibuye sichaze ngabakhombisi besifo sezimbombo zesifo seplasma cytokine/chemokine ezigulini ezimelana nekhambi le-TB ocwaningweni lwe-CAPRISA 020 InDEX. Izifo ezingosomathuba ze-TB/HIV ziholela ekukhuleni kokuphazamiseka kokusebenza kwesethi encane yenhlayiya ye-CD56neg NK. Ukuqedelwa ukwelashelwa i-TB kuholela ekwenziweni kabusha kwezinhlayiya ze-NK, ukusabalaliswa kabusha kwesethi encane ye-NK kanye nokulawulwa maphansi kwezinhlayiya eziningi ze-NK ezenza izamukeli zisebenze noma ziphazamiseke. Iphesenti eliphezulu lezinhlayiya ze-CD56bright zazihlobaniswa nesikhathi eside sokubonakala kwenguquko, ngenkathi izinga eliphezulu lokuziveza kwezinhlayiya ze-NKp46 ku-CD56dim NK kwakuhlobaniswa nezinga eliphansi lokubhoboka kwamaphaphu eqoqweni lonke labantu beminyaka elinganayo kanye nababambiqhaza abane-TB/HIV kodwa bebenezinye izifo ezibaphethe. Ngokwezimpendulo zenhlayiya yememori ye-CD4+ T, izifo mixhantela ye-TB/HIV kwaholela ephesentini eliphezulu lezinhlayiya ze-Th2, i-α4β1 ne-α4β7 i-integrin ikhombisa izinhlayiya zememori ye-CD4+ T nephesenti eliphansi lezinhlayiya ze-Th9. Ukukhula kokuziveza kwe- IL-6 ngesikhathi i-MDR/XDR-TB ihlobaniswa nobungozi bezinga eliphezulu bokubhoboka kwamaphaphu kubabambiqhaza be-CAPRISA 020. Ngaphezu kwalokho ukubhema nomlando owedlule we-TB wahlobaniswa nokukhula kobungcuphe kwesifo sezimbobo emaphashini ngenkathi i-HIV ne-BMI ephezulu kwahlobaniswa nokwehla kobungcuphe bezimbobo emaphashini ngesikhathi se- MDR/XDR TB. Sathola izinguquko ezibonakalayo zabasengcupheni ohlelweni lokuvuvukala, izinhlayiya ze-NK kanye nezinhlayiya ze-CD4+ T ngokwesifo esimandla, ukuqedelwa kokwelashwa, ukuqedwa kwegciwane nokuba mandla kwesifo se-TB ne-HIV kulowo onezinye izifo ezimphethe. Imiphumela yagqamisa iqiniso elikholekayo nendlela yokwelapha okuyiyona okubuye kube nokutheleleka nge-HIV ngesikhathi esisodwa okuyikhona okuphazamisa umgcinikulawulwa kwamasosha omzimba esifo seMtb.